Single-cell analysis identifies RETN+ monocyte-derived Resistin as a therapeutic target in hepatitis B virus-related acute-on-chronic liver failure

Abstract

Background: Acute-on-chronic liver failure (ACLF) is characterised by intense systemic inflammation and high short-term mortality, yet effective targeted therapies are lacking.

Objective: To explore monocyte heterogeneity in HBV-related ACLF (HBV-ACLF) to identify specific subsets and associated therapeutic targets.

Design: Peripheral blood mononuclear cells from healthy controls (n=4), patients with acute decompensation (n=5), and patients with ACLF (n=9) underwent single-cell RNA sequencing (scRNA-seq). Findings were integrated with hepatic scRNA-seq, bulk transcriptomics, multiplex immunohistochemistry and in vitro functional assays. The in vivo roles of candidate targets were validated in two murine ACLF models.

Results: We identified a distinct RETN⁺ monocyte subset that was expanded in the circulation and liver of patients with HBV-ACLF. These RETN⁺ monocytes displayed a transcriptional programme enriched for anti-inflammatory and pro-resolving signatures, including MS1-B-like features. Interleukin-6 promoted the expansion of RETN⁺ monocyte via the JAK/STAT3/RUNX1 signalling axis. In murine ACLF models, neutralisation of Resistin exacerbated liver injury, increased systemic cytokine levels and augmented hepatocyte apoptosis. Conversely, administration of recombinant Resistin mitigated liver damage, diminished levels of inflammatory cytokines and improved survival. Mechanistically, Resistin activated PI3K/AKT signalling in hepatocytes, preserved the Bcl-2/Bax balance and suppressed intrinsic apoptosis. Clinically, plasma Resistin levels in HBV-ACLF patients inversely correlated with systemic inflammatory markers, liver injury, ACLF severity scores (Model for End-Stage Liver Disease, Chronic Liver Failure Consortium ACLF score) and short-term mortality.

Conclusions: RETN⁺ monocytes constitute a distinct immunoregulatory subset enriched in HBV-ACLF, and their product, Resistin, exerts significant hepatoprotective and anti-inflammatory effects. These findings highlight RETN⁺ monocytes and Resistin as promising immunotherapeutic targets for HBV-ACLF.

Keywords: CIRRHOSIS; INFLAMMATION; LIVER FAILURE; SINGLE-CELL ANALYSIS.